Transdermal patch for external use comprising fentanyl

ABSTRACT

A transdermal patch for external use having a backing layer and a pressure-sensitive adhesive layer formed on one surface of the backing layer, which contains polyisobutylene, a mineral oil and fentanyl employed as the active ingredient in the pressure-sensitive adhesive layer and in which the contents of polyisobutylene and fentanyl in the pressure-sensitive adhesive layer respectively range from 75.2 to 94.2% by mass and 1 to 6% by mass while the content of the mineral oil is from 0.25 to 0.05 parts by mass based on polyisobutylene. This patch can be easily produced, has a long-lasting effect and is excellent in adhesion to the skin and tolerability against movement to the body parts.

DETAILED DESCRIPTION OF THE INVENTION

1. Technical Field

The invention relates to a patch which makes it possible to administerfentanyl for not less than two days and has an object of stability, skinpermeability and reduction of production cost. Specifically, theinvention relates to a transdermal patch for an external use, wherein itcontains polyisobutylene, a mineral oil and isopropyl myristate aspressure-sensitive adhesive agents and fentanyl.

2. Background Art

As a conventional fentanyl patch, there is a fentanyl patch ofreservoir-type (for example, see patent publication 1). However, thereservoir-type patch has demerits that due to enclosing a drug as asolution or semisolid into a drug reservoir, a highly precisepreparation step is required not to induce the volatilization andleakage of the content, and due to necessity of a drug releasecontrolling membrane in its structure a manufacturing process cannotavoid being complicated.

In addition, as to a fentanyl patch utilizing an ion-pair containing adrug salt and an organic acid salt, its mix pressure-sensitive adhesivebase material containing SIS and PIB are disclosed respectively (forexample, see patent publication 2 and patent publication 3). However,the ion-pair type patch also has demerits that due to necessity ofadding a large amount of an organic acid salt to form a stable ion-pair,there are many restrictions in conditions for the manufacturing process(milling, mixing, coating, drying) while the process is complicated, anddue to a high drug releasability or absorption, the progress of a drugdepletion during a drug application is rapid, and it is not apt for adrug efficacy continuity of a long term exceeding one day.

Further, although a fentanyl patch of monolithic type, which containspolyisobutylene and a mineral oil as pressure-sensitive adhesive agents,is also disclosed (for example, patent publication 1), saidpolyisobutylene pressure-sensitive adhesive layer contains fentanyl of10-30% in the pressure-sensitive adhesive layer, whereby in such a casethere is a concern that crystallization of fentanyl in the formulationoccurs as time passes by, and therefore, it is not practical from theview point of adhesion properties and a drug releasability.

On the other hand, it is known to use polyisobutylene as an adhesive.However, for example, in patent publication 4 said polyisobutylenepolymer is a adhesive to percutaneously administer an active substanceof oily and nonaqueous liquid, and thus it does not disclose atransdermal patch for external use comprising a solid active substanceat ordinary temperature like fentanyl, which in used in the presentinvention, and it has a problem with regard to such as adhesivenessbecause it does not contain a mineral oil (for example, see Non-patentpublication 1).

Patent Publication 1

-   -   JP, A, 61-37725 (page 1 to page 10)

Patent Publication 2

-   -   JP, A, 10-45570 (page 1 to page 10)

Patent Publication 3

-   -   JP, A, 2000-44476 (page 1 to page 8)

Patent Publication 4

-   -   JP, A, 5-507682 (page 1 to page 6)

Non-Patent Publication 1

-   -   Journal of Pharmaceutical Sciences, Vol. 85, No. 5, p 491, May        1996 by Samir D Roy et al.

DISCLOSURE OF THE INVENTION

Thus, an object of the invention is to provide a long-lastingtransdermal patch for external use comprising fentanyl wherein thereduction of production cost is possible because the patch can easily beproduced and the adhesion to the skin and tolerability against movementto the body parts of the formulation are improved comparing with thoseof conventional products, and further, it has high formulation stabilityand is excellent in the skin permeability.

As a result of extensive researches for solving the above objects, theinventors found out that by optimization of the mixing ratio of PIB, amineral oil and fentanyl the above objects can be solved, andaccomplished the invention.

Namely, the invention relates to a transdermal patch for external usehaving a backing layer and a pressure-sensitive adhesive layer formed onone surface of the backing layer, comprising polyisobutylene, a mineraloil and fentanyl employed as the active ingredient in thepressure-sensitive adhesive layer, the contents of polyisobutylene andfentanyl in the pressure-sensitive adhesive layer respectively rangingfrom 75.2 to 94.2% by mass and 1 to 6% by mass while the content of themineral oil being from 0.25 to 0.05 parts by mass based onpoyisobutylene.

In addition, the invention relates to the above patch, wherein thepolyisobutylene is a mixture of a high molecular weight polyisobutyleneof average molecular weight in a range from 800,000 to 1,600,000 and alow molecular weight polyisobutylene of an average molecular weight in arange from 30,000 to 80,000.

Further, the invention relates to the above patch, wherein the massratio between the high molecular weight polyisobutylene and the lowmolecular weight polyisobutylene is 1:9 to 2:3.

In addition, the invention relates to the above patch, wherein themineral oil is liquid paraffin.

Further, the invention relates to the above patch, wherein thepressure-sensitive adhesive layer further contains a percutaneousabsorption enhancer.

In addition, the invention relates to the above patch, wherein thepercutaneous absorption enhancer is one or more selected from a groupconsisting of isopropyl myristate, isopropyl palmitate, sorbitanmonooleate and oleyl alcohol.

Furthermore, the invention relates to the above patch, wherein it has anarea of 5 to 80 cm² at a time of application.

As described above, the transdermal patch for external use comprisingfentanyl of the invention has a pressure-sensitive adhesive agent on thebacking layer, wherein the pressure-sensitive adhesive agent comprises amixture of PIB and the mineral oil in a specified concentration, thatis, 1:0.25 to 1:0.05. By such a constitution, a long-term administrationof fentanyl becomes possible. Namely, according to the patch of theinvention blood concentration of fentanyl can be kept not less than 1ng/mL even at 48 to 72 hours after application. In addition, in thepatch of the invention there is no cohesion failure of apressure-sensitive adhesive agent and no remaining of an adhesive massto the skin, and, therefore, the burden of a patient due to a long-termadministration can be reduced.

Further, the transdermal patch for external use comprising fentanyl ofthe invention does not require a pressure-adhesive layer with a drugrelease controlling membrane as in a reservoir-type patch and achieveseasier set up of conditions of manufacturing processes (mixing, coating,drying) compared with those of an ion-pair type patch, and, therefore,can be produced by an easier process compared with a conventionaltransdermal patch for external use comprising fentanyl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a profile of plasma concentration of fentanyl in femalerabbits after a single transdermal administration of a patch of theinvention (Example 5).

MODES FOR CARRYING OUT THE INVENTION

In the following, the transdermal patch for external use comprisingfentanyl of the invention is further explained in detail.

A pharmacologically active substance in the transdermal patch forexternal use comprising fentanyl of the invention is fentanyl itself anddoes not contain a salt thereof. Said fentanyl is contained in thepressure-sensitive adhesive layer.

Further, fentanyl is preferably in 1 to 6% based on the total mass ofthe pressure-sensitive adhesive layer in the patch of the invention. Bythe content not less than 1% by mass it becomes easy to get a sufficientamount of permeation as a transdermal patch for external use, and bymaking not more than 6% by mass it is possible to surely exclude badeffects due to a crystallization for physical properties of theformulation itself.

The fentanyl content of 1 to 6% by mass is preferable because a highblood concentration can be obtained. In addition, the fentanyl contentfrom 1.5 to 2.5% by mass is particularly preferable in the aspects ofphysical properties of the formulation and of adhesiveness.

In addition, the pressure-sensitive adhesive agent of the patch of theinvention consists of PIB, and the content of PIB may range from 75.2 to94.2% by mass, preferably 80 to 94.2% by mass, more preferably 85 to 90%by mass. By the PIB content not less than 75.2% by mass, a sufficientadhesiveness can be obtained, andbynotmorethan94.2%bymass, thecohesionfailure of the pressure-sensitive adhesive agent and remaining of theadhesive mass to the skin can be avoided.

When PIB contains a high molecular weight PIB and a low molecular weightPIB, a function as a pressure-sensitive adhesive agent is achieved,which is preferable in the aspect of adhesion properties.

The viscosity average molecular weight (Flory) of the high molecularweight PIB is preferably 800,000 to 1,600,000, more preferably 900,000to 1,500,000, and particularly preferably 1,000,000 to 1,400.000.

In addition, the viscosity average molecular weight (Flory) of the lowmolecular weight PIB is preferably 30,000 to 80,000, more preferably35,000 to 70,000, and particularly preferably 35,000 to 60,000.

In addition, the mass ratio between the high molecular weightpolyisobutylene and the low molecular weight polyisobutylene ispreferably 1:9 to 2:3, more preferably 1:7 to 1:5.

The above mixing ratio of the high molecular weight polyisobutylene andthe low molecular weight polyisobutylene excludes the cohesion failureof the pressure-sensitive adhesive layer and remaining of the adhesivemass.

Meanwhile, the above average molecular weight is viscosity averagemolecular weight (Flory) measured by the viscosity method.

In the pressure-sensitive adhesive agent, the mineral oil is mixed inaddition to PIB as described above, though the concentration ratiothereof is 1:0.25 to 1:0.05, preferably 1:0.15 to 1:0.05, morepreferably 1:0.1 to 1:0.05. Mixing a mineral oil at said content enablesthe adhesive strength of a patch apt for a long-term administration,which is one of the objects in the invention can be obtained. As saidmineral oil, there is no limitation as long as it satisfies the aboveobject. Liquid paraffin is preferable.

Further, a percutaneous absorption enhancer for fentanyl may becontained in the pressure-sensitive adhesive agent of the patch of theinvention. As to said percutaneous absorption enhancer, it may be anyone or more compounds with which a percutaneous absorption enhancingeffect of a drug has been known. Examples include C₆-C₂₀ fatty acids,fatty alcohols, fatty acid esters, alkyl ethers, aromatic organic acids,aromatic alcohols, aromatic fatty acid esters and aryl ethers.Furthermore, the examples include those such as lactic acid esters,acetic acid esters, monoterpene type compounds, sesquiterpene typecompounds, Azone or its derivatives, glycerol fatty acid esters,sorbitan fatty acid esters, polysorbates, polyethylene glycol fattyacidesters, polyoxyethylene hardened castor oils, sucrose fatty acidesters.

Preferable examples include caprylic acid, capric acid, caproic acid,lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid,linoleic acid, linolenic acid, lauryl alcohol, myristyl alcohol, oleylalcohol, cetyl alcohol, methyl laurate, isopropyl myristate, myristylmyristate, octyl decyl myristate, cetyl palmitate, salicylic acid,methyl salicylate, glycol salicylate, cinnamic acid, methyl cinnamate,cresol, cetyl lactate, ethyl acetate, propyl acetate, isopropylpalmitate, sorbitan monooleate, geraniol, thymol, eugenol, terpineol,1-menthol, borneol, d-limonene, isoeugenol, isoborneol, nerol,d1-camphor, glycerol monolaurate, glycerol monooleate, sorbitanmonolaurate, sucrose monolaurate, polysorbate 20, polyethylene glycolmonolaurate, polyethylene glycol monostearate, HCO-60 (hardened casteroil), and 1-[2-(decylthio)ethyl]aza-cyclopentan-2-one (hereinafterabbreviated as pyrothiodecane), and in particular, fatty acid ester anda liphatic alcohol. In particular, isopropyl myristate, isopropylpalmitate, sorbitan monooleate and oleyl alcohol are preferred.

The above absorption enhancers may be blended in an amount of preferably0.01 to 20% by mass, more preferably 0.1 to 10% by mass and particularlypreferably 0.5 to 3% by mass based on the total mass of thepressure-sensitive adhesive layer in the formulation of the invention.The content of the absorption enhancer not more than 20% by massprevents skin irritation such as erythema and edema, and not less than0.01% by mass provides an effect of blending the absorption enhancer.

Further, in the patch of the invention, a hydrophilic polymer may beblended, if required, in order to absorb aqueous constituents such assweat from the skin. Preferred hydrophilic polymers include, forexample, light anhydrous silicic acid, cellulose derivatives[carboxymethyl cellulose (CMC), carboxymethyl cellulose sodium (CMCNa),methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC),hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC)], starchderivatives (pullulan), polyvinyl alcohol (PVA), polyvinylpyrrolidone(PVP), polyvinyl acetate (VA), carboxyvinyl polymer (CVP), ethylvinylacetate copolymer (EVA), Eudragit, gelatin, polyacrylic acid, sodiumpolyacrylate, polyisobutylene-maleic anhydride copolymer, alginic acid,sodium alginate, carrageenan, Arabian gum, tragacanth gum, karaya gumand polyvinyl methacrylate. In particular, light anhydrous silicic acid,cellulose derivatives (CMCNa, HPMC, HPC, MC) and Eudragit are preferred.The hydrophilic polymer may be blended preferably in 0.01 to 20% bymass, and particularly preferably 0.5 to 10% bymass based on the totalmass of the pressure-sensitive adhesive layer in the patch of theinvention.

In addition, if desired, other components such as a cross-linking agent,preservative and antioxidant maybe blended in the pressure-sensitiveadhesive layer in the patch of the invention. Preferable cross-linkingagents include thermosetting resins such as amino resins, phenol resins,epoxy resins, alkyd resins and unsaturated polyesters, isocyanatecompounds, block isocyanate compounds, organic type cross-linkingagents, and inorganic type cross-linking agents such as metals or metalcompounds. As the preservatives, those such as ethyl p-hydroxy benzoate,propyl p-hydroxy benzoate, butyl p-hydroxy benzoate are preferable. Asthe antioxidants, those such as tocopherol and its ester derivatives,ascorbic acid, ascorbic acid-stearic acid ester, nordihydroguareticacid, dibutyl hydroxy toluene (BHT), butyl hydroxy anisole (BHA) arepreferable. Further, the pressure-sensitive adhesive layer in the patchof the invention preferably consists of a nonaqueous base, higher effectof the invention being obtained with the nonaqueous base.

The pressure-sensitive adhesive layer in the patch of the inventionmaybe manufactured by any conventional methods. For example, in case ofmanufacturing by a solvent method, to an organic solvent solution of ablended polymer is added the other components and stirred, and then themixture is coated onto the backing layer and dried to obtain theformulation. Moreover, in a case that a blended polymer can be spread bya hot-melt method, the polymer ingredient is dissolved at hightemperature, then added with the other ingredients, stirred, and spreadon the backing layer to obtain the formulation of the invention.

In addition, in the patch of the invention, so long as thepressure-sensitive layer is constituted by the compositions as describedabove, and has a backing layer to support it, other layers oringredients to constitute these are not particularly limited, whereby itmay be constituted by any layers. For example, the patch of theinvention may contain in addition to the backing layer andpressure-sensitive adhesive layer, those such as a release liner layerset up on the pressure-sensitive adhesive layer.

The above backing layer may comprise, for example, fabric, nonwovenfabric, polyurethane, polyester, polyvinyl acetate, polyvinylidenechloride, polyethylene, polyethylene terephthalate, paper, an aluminumsheet and the like, or composite materials thereof.

As for the patch of the invention, fentanyl is absorbed through the skinfor a longer period compared with a conventional percutaneous absorptionformulation. Therefore, it provides a more effective method of painrelief for patients who have difficulties with oral administration ofnarcotic analgesic agents. In addition, since it can be administeredwithout invasion compared with a continues subcutaneous administrationmethod which is an invasive administration method, it can certainlyalleviate burdens of patients.

Further, the dose can easily be adjusted according to a patient'ssymptoms, age, body weight, sex by, for example, cutting the coatedproduct. Although the area of the patch of the invention when applyingis not particularly limited, it is preferably 5 to 80 cm², morepreferably 5 to 70 cm², further preferably5 to 45 cm². The areas of notmore than 80 cm² provides favorable handling when applying, and that ofnot less than 5 cm² enables a sufficient blood concentration of theeffective ingredient easily to be maintained.

EXAMPLE

In the following, the invention is explained in more detail by theexamples. The invention, however, is not limited to these examples, andvarious changes may be made without departing from the spirit of theinvention. Further, in the examples, ‘%’ means ‘% by mass’ unlessotherwise specified.

Example 1

High molecular PIB  31.0% Low molecular PIB  62.0% Liquid paraffin  5.0%Fentanyl  2.0% Total amount 100.0%

In the composition, liquid paraffin and fentanyl were stirred at roomtemperature, then added with toluene solution of base and stirred, andthen the mixture was coated onto a PET film and dried at 110° C. for 15min to give the pressure-sensitive adhesive layer of 50 μm, and thepatch of the invention was obtained by a conventional method.

In Examples 2-6 and Comparative examples 1-3, the contents of highmolecular PIB, low molecular PIB, liquid paraffin and fentanyl werechanged respectively as shown below and in Table 1, and the patches wereprepared in the same way as that of the example 1 except adjusting thecontents of the other ingredients accordingly.

Example 2

High molecular PIB  27.0% Low molecular PIB  63.0% Liquid paraffin  9.0%Fentanyl  1.0% Total amount 100.0%

Example 3

High molecular PIB  17.6% Low molecular PIB  70.4% Liquid paraffin  6.0%Fentanyl  6.0% Total amount 100.0%

Example 4

High molecular PIB  36.0% Low molecular PIB  54.0% Liquid paraffin  7.0%Fentanyl  3.0% Total amount 100.0%

Example 5

High molecular PIB  12.8% Low molecular PIB  76.7% Liquid paraffin  5.0%Isopropyl myristate  3.0% Fentanyl  2.5% Total amount 100.0%

Example 6

High molecular PIB  63.0% Low molecular PIB  27.0% Liquid paraffin  9.0%Fentanyl  1.0% Total amount 100.0%

Comparative Example 1

High molecular PIB  23.3% Low molecular PIB  46.7% Liquid paraffin 28.0% Fentanyl  2.0% Total amount 100.0%

Comparative Example 2

High molecular PIB  18.6% Low molecular PIB  74.4% Liquid paraffin  1.0%Fentanyl  6.0% Total amount 100.0%

Comparative Example 3

High molecular PIB  14.0% Low molecular PIB  56.0% Liquid paraffin 24.0% Fentanyl  6.0% Total amount 100.0%

Test Example

(Method)

Skin permeability, adhesive property, cohesive property, adhesion to theskin and remaining of adhesive mass to the skin (placebo used) of eachformulation as described above were evaluated by the following methods.In addition, the overall evaluation as the formulation performance wascarried out from both aspects of the skin permeability and the physicalproperties of the formulation based on the common standard.

(Skin Permeability Test)

Using each patch obtained in Examples 1-6 and Comparative Examples 1-3,the following tests were carried out.

First, a back part skin of a hairless mouse was extirpated, and thedermal side was placed to a receptor layer side and mounted on aflow-through cell in which warm water of 33° C. was circulated aroundthe outer part. Then, the patch (application area of the formulation: 5cm²) was stuck on the stratum corneum side of the skin, and samplingsfor the receptor solutions were carried out at every one hour for 12hours at a rate of 10 ml/ hr using the saline as the receptor layer,whereby the flow amounts were measured and also the drug concentrationswere measured by a high-performance liquid chromatography. The drugpermeation rates per hour were calculated from the measured values todetermine the drug permeation rates per unit area of the skin at asteady state. The maximum values of the drug permeation rate (maximumskin permeation rate) obtained during 12 hours from the start of thetest are shown in Table 1.

(Test for Physical Properties of Formulations)

As to each formulation in the examples 1-6 and the comparative Examples1-3, the adhesiveness was measured by a probe tack tester and a peelmeasuring instrument, and the cohesive properties and the adhesion tothe skin were measured by a creep measuring instrument respectively. Thephysical properties of the formulations were evaluated by the followingcriteria:

◯: Good

Δ: Suitable

×. Unsuitable

In addition, the overall evaluation as the formulation performance wascarried out from both aspects of the skin permeability and the physicalproperties of the formulation based on the same standard. The resultsobtained are shown in Table 1.

(Adhesion Test)

As to each formulation in the examples1-6and the Comparative Examples1-3, each placebo formulation of 40 cm² was applied to the chests of 10healthy male adult subjects for three days, and in the case that theremaining of the adhesive mass occurred when removing, the state wasdescribed.

(Pharmacokinetic Study in Rabbits)

The patch obtained in the example 5 was cut into sheets of 8 cm², and apharmacokinetic study was carried out in the following. Namely, onesheet of the above formulation was each applied on four rabbits ofJapanese White (18 week old, female, about 3 kg of body weight) whoseback was shaven, and removed after 72 hours. The plasma was collectedvia auricle vein at 1, 2, 4, 8, 12, 24, 48, 72, 74, 76 and 80 hoursafter sticking of the formulation, and the fentanyl concentration in theobtained plasma was measured by LC/MS/MS. The time—fentanylconcentration in the plasma profile was shown as mean±S.D. in FIG. 1.TABLE 1 Example Example Example Example Example Example ComparativeComparative Comparative 1 2 3 4 5 6 example 1 example 2 example 3 Highmolecular 31.0 27.0 17.6 36.0 12.8 63.0 23.3 18.6 14.0 PIB (%) Lowmolecular 62.0 63.0 70.4 54.0 76.7 27.0 46.7 74.4 56.0 PIB (%) Liquid31.0 9.0 6.0 7.0 5.0 9.0 28.0 1.0 24.0 paraffin (%) Isopropyl — — — —3.0 — — — — myristate (%) Fentanyl (%) 2.0 1.0 6.0 3.0 2.5 1.0 2.0 6.06.0 Total 100 100 100 100 100 100 100 100 100 Adhesion ◯ ◯ ◯ ◯ ◯ Δ ◯ X XAgglutinative ◯ ◯ ◯ ◯ ◯ ◯ ◯ ◯ X property Adhesive ◯ ◯ ◯ ◯ ◯ Δ ◯ X ◯Property Remaining of ◯ ◯ ◯ ◯ ◯ ◯ X ◯ X adhesive mass Skin 6.0 5.2 15.09.8 8.0 4.9 6.5 15.0 16.5 permeability (hairless mouse, μg/cm²/h)Overall ◯ ◯ ◯ ◯ ◯ Δ X X X evaluation(Results)

As shown in Table 1, the patch of the invention was excellent in any ofadhesive property, cohesive property, adhesion property and remaining ofadhesive mass to the skin. On the contrary, remaining of adhesive massto the skin occurred in Comparative Example 1 (PIB:Liquidparaffin=1:0.4) having higher liquid paraffin content than that of PIB,and adhesive property is not sufficient in Comparative Example 2 havingless content (PIB:Liquid paraffin=1:0.01). When the total amount of PIBis less than 75.2% by mass, it is difficult to obtain the formulation inview of the poor physical properties.

Meanwhile, as described above, the adhesive property, cohesive property,adhesion to the skin and remaining of adhesive mass to the skin wascompared among placebos, which were free from fentanyl. However, sincethe effect which fentanyl exerts on these physical properties is small,it is considered that the patch of the invention in which fentanyl isblended will also be excellent in the adhesive properties and theothers.

In addition, the patch of the invention showed a sufficient value in themaximum skin permeation rate, which is an indicator of skin permeability(Table 1).

From the above results, it was clearly understood that the patch of theinvention not only gives sufficient skin permeability of fentanyl, butalso is excellent in the adhesive property, cohesive property, adhesionto the skin and remaining of adhesive mass to the skin.

With the patch of the invention, the rabbit plasma concentration offentanyl reaches C_(MAX) at about 12 hours after application, theconcentration of not less than 1 ng/mL was kept till 72 hours afterapplication. Based on this result and the general information thatabsorbability and the time course of plasma concentration in case ofapplication of a fentanyl patch to the human skin is slower comparedwith those of rabbit (Otsuka et al, Parmacokinetics after subcutaneousor percutaneous administrations of fentanyl to rabbits, Jpn. Pharmacol.Ther. (Yakuri to Rinsyou), Vol.29, No.11, 2001, 887-897; Mizuguchi etal, Clinical evaluation of fentanyl patch (KJK-4263) toward cancer pain(1), Medicine and Drug Journal Vol.37, No.8, 2001/p. 2389-2402), it wasclearly understood that by the patch of the invention, fentanyl bloodconcentration could be kept not less than 1 ng/mL during 48 to 72 hoursafter application to patients.

INDUSTRIAL APPLICABILITY

According to the invention, the application as a transdermal patch forexternal use comprising fentanyl is provided, which can easily beproduced, has a long-lasting effect and is excellent in adhesion to theskin and tolerability against movement to the body parts.

1. A transdermal patch for external use having a backing layer and apressure-sensitive adhesive layer formed on one surface of the backinglayer, comprising polyisobutylene, a mineral oil and fentanyl an activeingredient in the pressure-sensitive adhesive layer, contents ofpolyisobutylene and fentanyl in the pressure-sensitive adhesive layerrespectively ranging from 75.2 to 94.2% by mass and 1 to 6% by masswhile the content of the mineral oil being from 0.25 to 0.05 parts bymass based on poyisobutylene.
 2. The patch according to claim 1, whereinthe polyisobutylene is a mixture of a high molecular weightpolyisobutylene of average molecular weight in a range from 800,000 to1,600,000 and a low molecular weight polyisobutylene of averagemolecular weight in a range from 30,000 to 80,000.
 3. The patchaccording to claim 2, wherein a mass ratio between the high molecularweight polyisobutylene and the low molecular weight polyisobutylene is1:9 to 2:3.
 4. The patch according to claim 1, wherein the mineral oilis liquid paraffin.
 5. The patch according to claim 1, wherein thepressure-sensitive adhesive layer further contains a percutaneousabsorption enhancer.
 6. The patch according to claim 5, wherein thepercutaneous absorption enhancer is one or more selected from a groupconsisting of isopropyl myristate, isopropyl palmitate, sorbitanmonooleate and oleyl alcohol.
 7. The patch according to claim 1, whereinthe patch has an area of 5 to 80 cm² at a time of application.
 8. Thepatch according to claim 2, wherein the mineral oil is liquid paraffin.9. The patch according to claim 3, wherein the mineral oil is liquidparaffin.
 10. The patch according to claim 2, wherein thepressure-sensitive adhesive layer further contains a percutaneousabsorption enhancer.
 11. The patch according to claim 3, wherein thepressure-sensitive adhesive layer further contains a percutaneousabsorption enhancer.
 12. The patch according to claim 4, wherein thepressure-sensitive adhesive layer further contains a percutaneousabsorption enhancer.
 13. The patch according to claim 2, wherein thepatch has an area of 5 to 80 cm² at a time of application.
 14. The patchaccording to claim 3, wherein the patch has an area of 5 to 80 cm² at atime of application.
 15. The patch according to claim 4, wherein thepatch has an area of 5 to 80 cm² at a time of application.
 16. The patchaccording to claim 5, wherein the patch has an area of 5 to 80 cm² at atime of application.
 17. The patch according to claim 6, wherein thepatch has an area of 5 to 80 cm² at a time of application.